I’m new to Rapamycin. I started with 1mg and built by 1mg a week, now on 10mg and that’s my ceiling. No side effects, no noticeable benefits.
I am confused as whether a break is needed. In the last two weeks I’ve heard authors in the field say 5 weeks on and 8 weeks off; and the 8 weeks on and find weeks off. Others seem to propose taking it without a break.
Can anyone shed some light on this? Why a break at all, and if there is a break, who does one know the appropriate break period?
there is no answer to that question. all u are going to get is opinions and no proof of anything.
Breaks are recommended so that you don’t inhibit your MTORC2. This can happen if your Rapa levels are too high for too long. Hence the breaks.
dan_hayes is leaning hard into cynicism here, but his response does highlight the challenges of dosing rapamycin for longevity. We do not have gold-standard RCTs comparing different dosing schedules of rapamycin, initiated at different ages, and tracked across the duration of every participant’s lives. Nor do we have shorter-term human studies comparing dosing schedules with a more tractable longevity-based readout (e.g. epigenetic age, burden of senescent cells, etc).
Does that mean all we have are “opinions and no proof of anything”? Nah. We can do better than that. Just because we don’t have the best evidence doesn’t mean we have no evidence. In fact, we have quite a lot of evidence: a PubMed search for “rapamycin” returns about 53,900 published papers—including 3,295 clinical trials and 1,991 randomized control trials.
The central challenge is that we have to repurpose the data in these studies, as they generally investigate rapamycin in the context of organ transplants or cancer. Still—the data are there for those willing and able to triangulate it.
The mTORC2 complex plays a central role in glucose homeostasis (Hagiwara et al. 2012), (Yuan et al. 2012), (Lamming et al. 2014), (Lamming et al. 2014b), (Arriola Apelo et al. 2020). Rapamycin’s ability to cause glucose intolerance and insulin resistance stems from its inhibition of mTORC2, not mTORC1 (Lamming et al. 2012). Happily, mTORC2 is insensitive to acute doses of rapamycin. Unhappily, mTORC2 takes a hit if rapamycin is around too long:
chronic exposure to rapamycin, while not affecting pre-existing mTORC2 [complexes], promotes rapamycin inhibition of free mTOR molecules, thus inhibiting the formation of new mTORC2 [complexes] (Sarbassov et al. 2006).
How confident are we that inhibiting mTORC2 is a bad thing?
In sharp contrast to mTORC1, inhibition of mTORC2 has mostly negative effects on lifespan […] Genetic inhibition of mTORC2 in one or more tissues of a mouse can result in frailty, hyperphagia, insulin resistance, hyperlipidemia, hypercholesterolemia, hyperglycemia, kyphosis and/or obesity […] Specific inhibition of mTORC1 in mice… did not result in hyperglycemia, impaired glucose tolerance, hyperlipidemia or hypercholesterolemia, again demonstrating that these negative effects are mediated at least in part by inhibition of mTORC2 (Mannick and Lamming 2023).
mTORC1 inhibitors… but not dual [mTORC1/2] inhibitors protect against inflammation-induced apoptosis, senescence, and matrix catabolism in human disc cells, which depends on Akt and autophagy induction (Kakiuchi et al. 2019).
What do we know about when rapamycin begins affecting mTORC2?
In male and female C57BL/6 mice, 16 weeks of oral rapamycin (2.24 mg/kg body weight/day ≈ 22.7 mg at 75 kg body weight) had no effect on the phosphorylation of Akt (Ser473) and PKCα (Ser657)—both targets of mTORC2—but decreased the phosphorylation of p70S6K (an mTORC1 target) by ~34% in whole brain lysates (Halloran et al. 2012). This indicates that, at least in the brain, concerns over rapamycin’s capacity to suppress of mTORC2 are not warranted.
In three-month-old male C57BL/6NTac mice, 7 days of intraperitoneal injection with high-dose rapamycin (10 mg/kg bodyweight ≈ 101.5 mg at 75 kg) inhibited mTORC2 (reduced pAkt/Akt) in the thymus, lungs, adipose tissue, and heart (Sarbassov et al. 2006). Consist with (Halloran et al. 2012), rapamycin did not inhibit mTORC2 in the brain.
Here’s a relevant figure from (Sarbassov et al. 2006). The first row shows the amount of phosphorylated Akt (an mTORC2 substrate). If mTORC2 is inhibited, we will see less phosphorylated Akt. You can see a marked decrease in the thymus, lungs, adipose tissue, and heart—after 7 days of intraperitoneal injection with high-dose rapamycin.
In 26-week-old male psPten–/– mice (n = 15), eight weeks of 3x weekly oral doses of a highly bioavailable nanoformulation of rapamycin called Rapatar appeared to increase the amount of phosphorylated Akt at both a low (~0.1 mg/kg rapamycin) and a high (~0.5 mg/kg rapamycin) dose, but only the high dose was significant (p = 0.02) (Antoch et al. 2020). The increase in pAkt could result from releasing mTORC1’s inhibition of IRS1/2 and mTORC2 (Rozengurt et al. 2014). Direct inhibition of mTORC2 has previously required higher doses: e.g. 10 mg/kg in (Halloran et al. 2012) and 8 mg/kg in (Schreiber et al. 2015). These results indicate that rapamycin causes a compensatory activation of Akt at doses below the threshold of mTORC2 inhibition. I suspect this increase in Akt underlies the mTOR rebound sometimes seen with rapamycin, but that’s a topic for another post.
In (Chen et al. 2010), a low concentration of rapamycin (10 nM) didn’t inhibit mTORC2 after 24 hours, while a high concentration (1000 nM) did. This paper used two different cell lines: DU-145 and MCF-7. We can roughly extrapolate these numbers to circulating levels of rapamycin in ng/mL. Here’s the math:
10 nM = 10/1000/1000/1000 = 0.00000001 M = mol/L
= 0.00000000001 mol/mL x 914.187 g/mol = 0.00000000914187 g/mL
= 9.14 ng/mL
The 1000 nM dose is 100x higher: 914 ng/mL. This gives us one piece of evidence suggesting that 9.14 ng/mL avoids mTORC2 inhibition. I welcome others to find other in vitro or ex vivo studies to add more nuance to the dosage range that avoids inhibiting mTORC2.
What human dosing data do we have?
the maximum-tolerated dose of oral rapamycin administered to adult cancer patients on a daily basis has been reported at ~6 mg/d, which results in a maximal plasma concentration of ~22 nM (Jimeno et al. 2008)
A circulating concentration of 4.74 ng/mL rapamycin showed clinical benefit to patients with familial adenomatous polyposis (Yuksekkaya et al. 2016).
For transplant patients, rapamycin’s therapeutic window is 5 to 15 ng/ml in whole blood (Burke et al. 2022).
Personally, a 12 mg dose of rapamycin taken with food yielded an approximate peak of 17.9 ng/mL three hours later. The blood level (ng/mL) achieved by a given dose (mg) varies widely from person to person, so everyone needs to get their own blood work done.
Takeaways
Unless human clinical data eventually says otherwise, design your dosing schedule to avoid inhibiting mTORC2. You’ll need some personal data points to assist with that. A peak rapamycin level of 10 ng/mL probably avoids inhibiting mTORC2.
Get three sirolimus/rapamycin blood tests: 3 hours after your dose (~peak), 7 days after your dose (potential trough), and 14 days after your dose (confirming the trough).
Design your dosing schedule based on the levels you see at 7 days and 14 days. Based on rapamycin’s half-life, I expect most people to have detectable levels at 7 days. I suspect that matters less for lower doses, as the ng/mL amount of rapamycin would likely be below the mTORC2 inhibition threshold. But for higher doses, 14 days is probably wiser. But personal blood work is necessary to determine those parameters.
I’m not currently aware of studies that provide significant insight on the duration of a “rapamycin vacation”. In female C57BL/6NCr mice, 15-months of intraperitoneal injection with 1.5 mg/kg rapamycin, 3 times a week every other week, resulted in sustained mTOR suppression in the heart when measured 13 days after the last dose (Leontieva et al. 2014). The same dose given orally did not have that effect. So, either 13 days was sufficient to restore normal mTOR signaling in mice—or that dose never substantially lowered it to begin with. If anyone is familiar with studies that could shed light on the duration of a dosage break, please join in. As it stands, I don’t think mTORC2 signaling would present an argument for breaks longer than two weeks. But it may turn out to help reduce rapamycin’s other side-effects (e.g. hyperlipidemia). In that case, personal blood work to monitor ApoB would help direct the frequency and duration of rapamycin breaks.
Currently, I prefer an alternating schedule with rapamycin (Week 1), 24-36 hour fast (Week 2), rapamycin (Week 3), 24-36 hour fast (Week 4), break (Week 5), then repeat. But I will update and tweak that based on 1) new evidence and 2) my own blood work.
I didn’t intend to spend the morning writing this, but there you have it! We do not have definitive answers, but we’re miles and miles ahead of having nothing to go on. Bottom Line: We know enough to design more and less rational dosing schedules.
@McAlister wow, that’s a lot of data and you make reasonable points. The problem is, does data from mice apply to humans? Especially data from the brain with questionable about blood brain barrier issues. Does mtorc2 relate to height or duration of Rapa blood levels? What is the pur of a 2 week Rapa level?
I think @dan_hayes is still closer to the correct answer. We generally pick 6 mg as a dose because scientists studying this picked that as a wild as guess based on mouse studies.
Thank you! … not sure how long you invested in that response but it’s very useful.
Meh, he’s right. I have been following Drs Greene and Blagosklonny for two years and reading the papers referred to by forum members. The recommended schedules are from everyday continuous dosing to things like 8 weeks on 8 weeks off and everything in between. Low dose, high pulse dose, etc. I have tried several of the protocols and found the sweet spot for me is 1mg daily for one week, then one week off. This is the dose that does not cause any of my tested markers to be outside of the normal range. By putting my markers into the problematic age tests, Levine spreadsheet, Aging.ai, etc., my age delta is the best it has ever been. -12 to16 years.
I think keeping an eye on your health markers and side effects from taking rapamycin is the way for most people to determine their rapamycin doses and frequency. When I started rapamycin with very high pulse dosing, as that was a popular protocol at the time, I had side effects that I wouldn’t want to continue with. This also, temporarily, thank goodness, reduced my age delta in the aging tests. In addition, it sent many of my markers outside of the clinically accepted ideal ranges. Regardless of some saying, “Hey you’re taking rapamycin, you will live longer, so it doesn’t matter”, it matters to me.
My current belief is to take your rapamycin while keeping your markers good and you will live even longer.
I agree with @desertshores philosophy with the addition to never hesitate to stop if you feel off. And never let yourself think a week or a month off will hurt you or cost you anything. (This is the rapa philosophy I’m trying to adopt against my addictive instincts).
I broadly agree with that approach. It makes good sense to update your rapamycin dose based on well-established clinical markers. And I’m glad to hear the low-dose daily approach is working well for you. I also agree that the “recommended schedules” I’ve seen here and elsewhere cover the spectrum from low-dose continuous to high-dose intermittent. Expert opinions (like those of Dr. Greene or Dr. Blagosklonny) have value, but I’m really only interested in the evidence they’re basing those recommendations on.
I want to emphasize that an abundance of proposed schedules ≠ all schedules are equally well-supported or rational. It’s easy (and fun) to speculate. It takes much more work to tether your claims to evidence. Using mTORC2 inhibition as an example, I think the evidence carves out two potential routes: 1) low doses that stay below the mTORC2 inhibition threshold (especially locally within the stomach and intestines vs. systemically in circulation) and 2) intermittent higher doses that avoid a prolonged rapamycin exposure above the mTORC2 inhibition threshold.
I think your positive experience with option (1) above is a useful data point.
I have been wanting to have this discussion in the forum, thank you!
It’s all guesswork. The theory is that you don’t want to impede mTORC2 so you want it to go to zero before re-up. Blagosklonny has said it’s 50 to 50 for either taking weekly or daily, for instance. And he disputes that mTORC2 is inhibited (said just a few cell lines). And there is one expert who is taking 1mg daily. Peter Attia is on weekly one dose. What made you decide to take rapa and how’s going so far? What else you are taking for what purposes if you don’t mind sharing?
Thanks for the feedback.
How much rapamycin inhibits mTORC2 is still up for debate.
When I was taking high doses, up to 20mg w/GFJ, the only thing I experienced other than diarrhea, was a little slower wound healing and some thinning of my fingernails. I am 82, so you would think my immune system wouldn’t be as robust as a younger person’s. In the almost two years that I have been taking rapamycin, I have had no illnesses, colds, flu, or tested positive for COVID-19, etc.
I think major depression of mTOR2 from the doses that members are taking is unlikely.
But, that is just my opinion from reading various papers. I have no medical background.
Yes - I completely agree with this.
I think you want either frequent very low dosing (think 1/2 to 1 mg per day range, depending on weight) or (and this is the much more common approach) pulsed weekly, or every two weeks… much higher dosing… somewhere between 3mg for light/more sensitive people to 20mg every two weeks or so, seems to be the range that is working with people.
I don’t think I’ve seen any evidence to suggest that mTORC2 inhibition is a positive thing for longevity. A number of studies suggesting increased mTORC2 levels might be helpful for longevity.
In fact, this recent research has got me more interested in fasting simultaneous to rapamycin use, as it seems that the fasting could boost mTORC2 while you’re suppressing mTORC1 with rapamycin, which seems to me might be the optimal approach:
As I have posted several times, you can measure mTORC2.
Attached is a PDF copy of the paper;
truillet2016.pdf (1.2 MB)
No doubt, but I am looking for studies that measure suppression vs. dose.
Since we know rapamycin suppressing neutrophil to some degree, why don’t we use the range of neutrophil as a practical indication of whether you are on the right dosing regimen or not? Neutrophil is an innate immunity response. @RapAdmin @desertshores
I start on dosing with a hypothesis as to the mechanism we are trying to operate. I think that mechanism is improving the ATP/O efficiency of mitochondria via a route of encouraging mitophagy followed by some mitochondrial fission.
Hence there is a question as to how frequently do we want this to happen. I would personally think that it is not essential for it to happen every week or every fortnight. One would assume there is a stochastic element to this as well. Hence as a consequence of mTORC1 inhibition a proportion of cells (higher than otherwise) get some BECLIN1 created and this kicks off mitophagy.
Hence my approach which differs from everyone else. I look every so often to have a period when I am encouraging mitophagy. Although when I stabilise (I was on holiday, I had a gig yesterday at a beer festival and I have been attending another festival Friday, Saturday and Sunday, hence I am not fasting although still reserving carbs to alcohol consumption) I will probably reinstate two fasting days a week. Probably once a month I will take Rapamycin on one of those days.
There is an interesting, but complex protocol on Longecity about mitochondrial fission and fusion based around C60, but it looks to potentially have hazards so I wish to study that as an additional technique for improving mitochondria. (when I have got through all of my other ideas)
I hypothesise that because BECLN1 is a long gene it probably requires a high level of acetyl-CoA and also a goodly quantity of ATP to be available to enable the cell to kick off autophagy. Hence I intend thinking carefully about how to achieve this. (It it is at all possible).
I was referring specifically to the cycling schedule which was the original poster’s issue NOT to anything and everything else about rapamycin such as dosage etc. even though it may relate in some sense or order to other aspects.
Is there a collected summary of age tests somewhere on this forum?